The Editors Respond: The Diminishing Role of Montelukast in Asthma Therapy

We greatly appreciate the additional opportunity to examine the therapeutic value of montelukast in particular and the leukotriene modifiers in general. The true value for money spent on montelukast is a subject of interest to virtually every managed care clinician and administrative pharmacist, as montelukast generated $2.976 billion in worldwide sales for the manufacturer in 2005, up 13.5% from $2.622 billion in 2004. Montelukast was cited in the company's 2005 annual report as the leader in sales performance, among its portfolio of products, and montelukast is projected to be the leading product in sales for the manufacturer through 2009. Montelukast costs about $1,100 per patient per year at discounted managed care organization prices in the United States in 2006; in the 3 months ending May 31, 2006, it pushed its way to be the overall fourth-highest expenditure drug. Any potentially negative information about montelukast would understandably be of great concern to the manufacturer and its employees.


The Editors Respond: ■■ The Diminishing Role of Montelukast in Asthma Therapy
We greatly appreciate the additional opportunity to examine the therapeutic value of montelukast in particular and the leukotriene modifiers in general. The true value for money spent on montelukast is a subject of interest to virtually every managed care clinician and administrative pharmacist, as montelukast generated $2.976 billion in worldwide sales for the manufacturer in 2005, up 13.5% from $2.622 billion in 2004. Montelukast was cited in the company' s 2005 annual report as the leader in sales performance, among its portfolio of products, 1 and montelukast is projected to be the leading product in sales for the manufacturer through 2009. 2 Montelukast costs about $1,100 per patient per year at discounted managed care organization prices in the United States in 2006; in the 3 months ending May 31, 2006, it pushed its way to be the overall fourth-highest expenditure drug. 3 Any potentially negative information about montelukast would understandably be of great concern to the manufacturer and its employees.
Markson and colleagues take issue with our use of the term "recommended" in describing, in the National Asthma Education and Prevention Program (NAEPP) guidelines, the place in therapy for the leukotriene modifiers in treating asthma, particularly in children. The NAEPP Expert Panel Report in 2002 (NAEPP EPR-2) recommends a step-wise approach to asthma management in adults and children. Nowhere in the NAEPP EPR-2 is a leukotriene receptor antagonist listed as preferred therapy. 4 The NAEPP EPR-2 makes a clear and unmistakable distinction between "preferred treatment" and "alternative treatment." 5 Markson et al. are right in implying that Curtiss could have been more accurate, by stating that the leukotriene modifiers are not recommended as preferred treatment in any category of asthma management in the NAEPP EPR-2.
The place in therapy for asthma occupied by the leukotriene modifiers in general and for montelukast in particular predicts bias in patient selection in a study of administrative claims data. Allen-Ramey et al. compared montelukast to salmeterol as add-on therapy from July 1, 1999, through June 30, 2000, a period of time prior to the market introduction of combination salmeterol-fluticasone in September 2000. 6 That is, the leukotriene modifiers are most likely to be used in patients with mild asthma, as suggested by the severity of illness data reported by Allen-Ramey et al. and which they attempted to address via patient matching using propensity scores. Despite label warnings of the potential for more-severe asthma attacks with the long-acting beta-2 adrenergic agonists (LABAs), 7 the preponderance of evidence and all asthma management guidelines recommend the preferre d use of prophylaxis with LABAs plus inhaled corticosteroid (ICS) in patients with moderate or severe disease. And although the authors highlight the release date of current guidelines predating 2006 publication of the Letters Salmeterol Multicenter Asthma Research Trial (SMART) study findings, the same issue of the journal, Chest, included an extensive evidence review by O'Byrne and Adelroth, which concluded, "LABAs in combination with ICSs remain the most effective asthma treatment currently available." 8 We also appreciate Markson and colleagues bringing attention to their attempt to classify disease severity scores from pharmacy claims. Closer examination of the unpublished severity of disease assessment system, which Crownover correctly identified as not validated, 9 defines the second-most severe group (Group 3) for example as the use of either 2 or more pharmacy claims for oral corticosteroids (OCs) or no OC pharmacy claims and 6 or more pharmacy claims for short-acting betaagonists (SABAs, e.g., albuterol) or 1 pharmacy claim for an OC and 4 or more SABA pharmacy claims. We prefer to let readers judge whether no OC pharmacy claims and 6 or more SABA claims in 12 months accurately represents Step 3 Moderate Persistent Asthma, defined by the NAEPP EPR-2 as daily symptoms, exacerbations affecting activity occurring at least twice per week, night symptoms more than once weekly, daily short-acting requirement for SABAs, and peak expiratory flow variability more than 30%. Since the proxy classification scheme was used to "obtain comparable groups," its accuracy is crucial to assess baseline status in each design arm. We acknowledge that the authors did, in fact, state that their proxy for asthma severity was included, with 10 other variables, in their propensity score logistic regression model and, upon further consideration, agree that post hoc "analysis" did not occur, only post hoc elaboration.
We are not persuaded by the criticism of the focus by Curtiss on SABA use. 10 The claim by Markson et al. that the higher use of SABAs in the ICS-montelukast group represents only "approximately 1.2 canisters per person per year (4.36 versus 3.16)" is, in fact, 38% higher relative use of SABAs. We also take the position that SABA use is arguably more clinically relevant and significant since SABA use is a common clinical marker used by physicians and can be used to detect poor asthma control prior to hospital or emergency department admission.
We also assert that a red herring is created by the notion that total beta-agonist use is a measure worth pursuing. This would represent the epitome of mixing apples and oranges since LABAs are used for prevention of attacks while SABAs are used to abort acute asthma attacks. No conundrum is produced by the absence of an "agreed-upon method to measure total betaagonist use," and we disagree that "interpreting SABA use alone is difficult in patients using LABA." We note that the Markson et al. do not dispute that perhaps only 25% of cases (the more severe cases by the proxy measure) potentially met NAEPP EPR-2 criteria for use of montelukast as an adjunct to ICS; these 25% were the only ones that undeniably should have been included in their analysis. Rather, the authors contend that deleting 75% of the cases (falling into the mild disease category) that matched between the treatment groups would not be representative of how these products were being used in clinical practice during the time frame of their study. While this may be true, what value is gained by retrospectively assessing outcomes for add-on medications being used improperly in patients with unconfirmed disease severity; i.e., medications indicated for moderate-severe disease used in patients with mild disease? The editors are reminded of a drug utilization review of azithromycin in which 50% of use was determined to be inappropriate. Some progress notes from the emergency department even listed "viral URI (upper respiratory infection)" as the diagnosis that accompanied the order for azithromycin. Evaluating the hospital admission rates in the 50% of patients who received azithromycin inappropriately may discover lower hospital use rates (in patients who received azithromycin for mild viral URIs), but would not inform since we care about the outcomes in the 50% of patients with moderate/severe infections who had indications for the appropriate use of azithromycin.
So, the evidence is what it is. Analysis of administrative claims data cannot be used to change the fact that montelukast is secondline or third-line therapy in asthma disease management. It is more appropriate for monotherapy in mild disease, but the evidence does not support primary use, even in this population of asthma patients. Based upon the available evidence, montelukast appears to be little more than an expensive placebo in disease management of moderate persistent asthma.
Leaving behind the current debate on the value of leukotriene modifiers, a potential vision for future asthma management may include symptom-driven intermittment corticosteroid therapy. For patients with mild persistent asthma, Boushey et al., writing for the Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute in 2005, advocated this far-reaching departure from current guidelines. 11 Also in 2005, Greaves et al. added further dimension by recommending that symptom-directed and patient-initiated dose reduction of corticosteroid therapy should be considered for mild asthma, since nonadherence to drug therapy produced outcomes for mild asthma patients similar to those for daily adherence. This is important new evidence for asthma population management in which nearly 3 of 4 patients have mild disease. 12,13 It potentially further shrinks the role of the leukotriene modifiers and could reduce ICS costs. 14 Brian K. Crownover

DISCLOSURES
Crownover is a board-certified family physician assigned to Eglin AFB Florida, where he serves as Family Medicine Residency program director, HQ Air Armament Center. Curtiss is an employee of the Academy of Managed Care Pharmacy (AMCP). The opinions and assertions contained herein are the private views of the editors and are not to be construed as official or as reflecting the views of any organization, including the U.S. Air Force medical department, the U.S. Air Force, or AMCP. Both editors disclose no potential bias or conflict of interest relating to this editorial.